ascorbic-acid and Fetal-Hypoxia

Topics: Acidosis; Animals; Ascorbic Acid; Blood Glucose; Brain; Dogs; Drug Therapy, Combination; Embryonic and Fetal Development; Female; Fetal Blood; Fetal Growth Retardation; Fetal Hypoxia; Glucose; Humans; Insulin; Insulin Secretion; Maltose; Maternal-Fetal Exchange; Oxygen Inhalation Therapy; Placenta; Placental Lactogen; Pregnancy; Sheep; Thiamine Pyrophosphate

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.

Topics: Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Atrophy; Dietary Supplements; Disease Models, Animal; Female; Fetal Growth Retardation; Fetal Hypoxia; Hippocampus; Male; Memory Disorders; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar

Evidence derived from human clinical studies and experimental animal models shows a causal relationship between adverse pregnancy and increased cardiovascular disease in the adult offspring. However, translational studies isolating mechanisms to design intervention are lacking. Sheep and humans share similar precocial developmental milestones in cardiovascular anatomy and physiology. We tested the hypothesis in sheep that maternal treatment with antioxidants protects against fetal growth restriction and programmed hypertension in adulthood in gestation complicated by chronic fetal hypoxia, the most common adverse consequence in human pregnancy. Using bespoke isobaric chambers, chronically catheterized sheep carrying singletons underwent normoxia or hypoxia (10% oxygen [O2]) ± vitamin C treatment (maternal 200 mg.kg-1 IV daily) for the last third of gestation. In one cohort, the maternal arterial blood gas status, the value at which 50% of the maternal hemoglobin is saturated with oxygen (P50), nitric oxide (NO) bioavailability, oxidative stress, and antioxidant capacity were determined. In another, naturally delivered offspring were raised under normoxia until early adulthood (9 months). Lambs were chronically instrumented and cardiovascular function tested in vivo. Following euthanasia, femoral arterial segments were isolated and endothelial function determined by wire myography. Hypoxic pregnancy induced fetal growth restriction and fetal oxidative stress. At adulthood, it programmed hypertension by enhancing vasoconstrictor reactivity and impairing NO-independent endothelial function. Maternal vitamin C in hypoxic pregnancy improved transplacental oxygenation and enhanced fetal antioxidant capacity while increasing NO bioavailability, offsetting constrictor hyper-reactivity and replenishing endothelial function in the adult offspring. These discoveries provide novel insight into mechanisms and interventions against fetal growth restriction and adult-onset programmed hypertension in an animal model of complicated pregnancy in a species of similar temporal developmental milestones to humans.

Topics: Animals; Antioxidants; Ascorbic Acid; Female; Fetal Growth Retardation; Fetal Hypoxia; Hypertension; Hypoxia; Nitric Oxide; Oxidative Stress; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Sheep

Fetal hypoxia is common and in vitro evidence supports its role in the programming of adult cardiovascular dysfunction through the generation of oxidative stress. Whether fetal chronic hypoxia programmes alterations in cardiovascular control in vivo, and if these alterations can be prevented by antioxidant treatment, is unknown. This study investigated the effects of prenatal fetal hypoxia, with and without maternal supplementation with vitamin C, on basal and stimulated cardiovascular function in vivo in the adult offspring at 4 months of age in the rat.. From days 6 to 20 of pregnancy, Wistar rats were subjected to Normoxia, Hypoxia (13% O2), Hypoxia+Vitamin C (5mg/ml in drinking water) or Normoxia+Vitamin C. At 4 months, male offspring were instrumented under urethane anaesthesia. Basal mean arterial blood pressure, heart rate and heart rate variability (HRV) were assessed, and stimulated baroreflex curves were generated with phenylephrine and sodium nitroprusside. Chronic fetal hypoxia increased the LF/HF HRV ratio and baroreflex gain, effects prevented by vitamin C administration during pregnancy.. Chronic intrauterine hypoxia programmes cardiovascular dysfunction in vivo in adult rat offspring; effects ameliorated by maternal treatment with vitamin C. The data support a role for fetal chronic hypoxia programming cardiovascular dysfunction in the adult rat offspring in vivo through the generation of oxidative stress in utero. 

Topics: Animals; Antioxidants; Ascorbic Acid; Cardiovascular Diseases; Female; Fetal Hypoxia; Hypoxia; Male; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Time Factors

The antioxidants, Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, a water soluble analog of vitamin E) and ascorbic acid (AA), protect the heart from ischemia-reperfusion injury. We hypothesized that maternal infusion of Trolox and AA, would reduce the fetal bradycardia and myocardial damage observed in fetal hypoxia and increase the total antioxidant activity in fetal plasma. Either i.v. saline (control group) or Trolox + AA (drug group) was randomly administered to 29-d-old pregnant rabbits. Fetal hypoxia was induced by uterine ischemia. Fetal heart rate, plasma CK-MB activity, and plasma total radical antioxidant potential (TRAP) were measured in different sets of animals. Fetal heart rate in the drug group was higher than in the control group for the first 35 min (p < 0.05 at every 5-min interval). Fetal bradycardia (<60 beats/min) occurred after 39 min (median) in the drug group, and 29 min in the control group (p < 0.05). After 50 min of hypoxia, plasma CK-MB was lower in the drug group, 1204 +/- 132 U/L (mean +/- SEM), than in the control group, 2633 +/- 233 U/L (p < 0.05). TRAP was higher in the drug group, 3.01 +/- 0.15 mM (Trolox equivalent concentration), than in the control group, 1.48 +/- 0.27 mM (p < 0.05). Higher TRAP levels (> or = 2.0 mM) were associated with lower CK-MB levels (<2500 U/L) (p < 0.05). Administration of Trolox and AA to the mother has a beneficial effect on fetal myocardial damage after fetal hypoxia, and a small beneficial effect on fetal bradycardia during hypoxia. The beneficial effect may be due to the augmentation of fetal plasma antioxidants from maternal antioxidant pretreatment.

Topics: Animals; Antioxidants; Ascorbic Acid; Bradycardia; Chromans; Creatine Kinase; Female; Fetal Hypoxia; Heart; Pregnancy; Rabbits; Reperfusion Injury; Survival

A study was made of lipid, cholesterol, and ascorbic acid content in the adrenal cortex of rabbit fetuses developing under conditions of normal pregnancy and under the action of hypoxic and hyperoxic exposures during its third trimester. It appeared that in normal pregnancy the adrenal cortex was activated, this being associated with the adaptive motor reactions of the developing fetus. The action of moderate hypoxic exposures led to a greater activation of moderate hypoxic exposures led to a greater activation of the adrenal cortex, this being expressed in a marked fall of lipid, cholesterol and ascorbic acid content. The weight of the total muscle mass and of the fetuses increased as a whole. The adrenal cortex became disactivated under conditions of the hyperoxic exposures; this is expressed in a marked increase in the content of the mentioned formations. The weight of the total mass and of the fetuses decreases.

Topics: Adrenal Cortex; Adrenal Glands; Animals; Ascorbic Acid; Cholesterol; Female; Fetal Hypoxia; Histocytochemistry; Lipid Metabolism; Oxygen; Pregnancy; Rabbits